Quaternary salt derivatives of harman



United States Patent O QUATERNARY SALT DERIVATIVES F HARMAN William M.McLamore, Kew Gardens, N. Y., assignor to Chas. Pfizer & Co., Brooklyn,N. Y., a corporation of Delaware No Drawing. Original applicationJanuary 30, 1956, Serial No. 562,026. Divided and this application March1, 1957, Serial No. 643,244

Claims. (Cl. 167-65) This invention is concerned with a unique group ofsubstituted ammonium salts useful as therapeutic agents. In particular,they are monosalts and are derivatives of barman and1,2,3,4-tetrahydroharman. They have the unique property of causing atherapeutically useful lowering of the blood pressure of an animal whenadministered thereto.

Various compounds have been suggested from time to time, in the past,for use in the therapy of hypertension. Some of these useful compoundsare quaternary ammo nium salts. However, these hypotensive quaternaryammonium salts known to the art are distinguished from the valuablesubstituted mono-ammonium salts of this invention in that they arebis-quaternary ammonium salts such as hexamethonium chloride which isthe bisquaternary ammonium salt, N,N,N',N'-tetra.methyl-1,6-hexanediamine dimethochloride. Heretofore, substituted mono-ammoniumsalts have not been found useful in the therapy of hypertension. Infact, attempts to find useful agents among the mono-ammonium salts inthe past have met with disappointment. It is therefore surprising thatit has now been found that certain substituted mono-ammonium salts havea particularly valuable com-a bination of pharmacohynamic propertieswhich makes vasodilator activity which makes them particularly useful ashypotensive agents. In addition, they have a remarkably low degree oftroublesome side effects including the cardiac effects referred toabove.

The valuable mono-ammonium salts of this type have the followingstructural formulas R: Qxe

N-CH R4 2,8193%! Patented Jan. 14, 1953 rue This application is adivisional application of copending application Serial Number 562,026filed January 30, 1956 in which the salts of Formula III are claimed.Those materials represented by Formula II are claimed in the presentapplication. In the foregoing structural formulas R is either a lowerhydrocarbonoxy group containing up to about six carbon atoms or it isthe --NHCH CH NL group wherein L is a lower alkyl group containing up toabout three carbon atoms such as methyl, ethyl or propyl. By lowerhydrocarbonoxy group is meant groups such as the methoxy group, theethoxy group, the butoxy group, the isobutoxy group and the hexoxygroup. These hydrocarbonoxy groups are substantially saturated but theymay contain some unsaturated linkages such as in the allyloxy group. Ris either a hydrogen atom or a lower aliphatic hydrocarbon groupcontaining up to about six carbon atoms. The lower aliphatic hydrocarbongroupsare such groups as methyl, ethyl, allyl, butyl and hexyl againsubstantially saturated but which may contain a minor proportion ofunsaturated linkages. At least two to four of the substituents R R R Rand R attached to the nucleus of the benzyl group in Formulas I and IIIare hydrogens, and the remainder are selected from the group consistingof a halogen atom, that is a fluorine, a chlorine, a bromine or aniodine atom and a lower hydrocarbonoxy group containing up to about sixcarbon atoms as defined above. In other words, at least one and not morethan three of these groups are substituents other than hydrogen. R is ahydrogen atom or a lower hydrocarbonoxy group containing up to about sixcarbon atoms. Some examples of such groups appear above. X is apharmacologically acceptable anion. By pharmacologically acceptableanion is meant an anion which is well tolerated in the dosages employedwith the products of this invention. Examples of pharmacologicallyacceptable anions are chloride,'

bromide, sulfate, methosulfate, phosphate, citrate, tartrate gluconate,succinate, etc.

These compounds are readily prepared by treating the parent nitrogenousbase with the appropriate quaternizing agent. Appropriate quaternizingagents include aliphatic hydrocarbon halides, sulfates, and sulfonatesin which the organic portion of the molecule corresponds to in the abovestructural formulas. Examples of useful quaternizing agents includemethyl iodide, dimethylsulfate, ethyl bromide, diethyl sulfate,m-methoxybenzyl bromide, 3,4-dichlorobenzyl bromide,3,4.-dimethoxybenzyl p-toluene sulfonate, p-rnethoxybenzyl chloride,p-ethoxybenzyl methanesulfonate, etc.

The treatment of barman with methyl bromoacetate to yield one of thesevaluable substituted mono-ammonium salts is represented in theaccompanying equation which illustrates the quaternization process.

(1 i N BICHzCOzCH;

NGHaCO2C a H Harman, the nitrogen compounds employed in preparing thismono-quaternary is prepared synthetically by the cyclodehydration,decarboxylation, and dehydrogenation of N-acetyl-dl-tryptophan bymethods well known in the art employing various dehydrating agents suchas phosphoryl chloride, polyphosphoric acid, etc. This process isillustrated by the following equation CH2CHGO2H NHCOCH: N N H H (I)Similar processes are known which employ tryptophan or tryptamine andacetaldehyde as starting materials. In the tetrahydroharman seriesFormula III wherein R is 70 compound of Formula II wherein a hydrogenatom, py-N-methylal,2,3,4-tetrahydroharman(1,Z-di-rnethyl-l,2,3,4-tetrahydr-B-carboliue) was treated with a seriesof substituted benzyl halides, sulfates, and sulfonates according tothey following'equation wherein Py-N-methyl-l,2,3,4-tetrahydroharman wasprepared by the reduction of harman methobromide or the anhydronium basepy-Nmethylharman by a standard known procedure. With the anhydroniumbase, catalytic hydrogenation employing a platinum catalyst was the mostsatisfactory method forcarrying out the reduction while sodiumborohydride was the most satisfactory agent for reducing themethobromide salt. These processes are illustrated below.

The parent bases in the tetrahydro series (Formula 111) wherein R is alower hydrocarbonoxy group are readily prepared by analogous proceduresfrom the O-alkylated harmalol derivatives which are known compounds.Harmalol is obtained by demethylation of harmaline, one of the Harmalaalkaloids. This series is illustrated below wherein R stands for thelower hydrocarbonoxy group of F of Formula 111.

Two of the compounds were prepared by special procedures. In the harmanseries, for the preparation of the the monoquaternary ammonium saltderived from her man and methyl bromoacetate, described above, was

R R R R and R have the same meanings as above. treated withZ-diethylaminoethyl amine which resulted in the formation of the desiredamide as is illustrated in the following equation.

In the tetrahydroharman series, Formula III, the compound wherein R =OCHand the remaining R groups are hydrogens was prepared by treating harmanwith m-methoxybenzyl bromide and reducing the so-obtained material withsodium borohydride. This process is illustrated by the followingequation.

OCH:

In the above quaternization processes the anion X is usually either ahalogen anion such as chloride, bromide or iodide or an organic sulfateor sulfonate anion such as methosulfate, ethosulfate, benzenesulfonate,or paratoluenesulfonate. These anions may be replaced by otherpharmaceutically acceptable anions such as the phosphate, succinate,citrate, or tartrate by various processes well known in the art. Forexample, with the quaternary salts, the salt may be converted to thequaternary ammonium hydroxide by treatment with silver oxide or'bypassage through a column of a strongly basic anion exchange resin on thehydroxide cycle. Examples of useful ion exchange resins are Dowex 1,Dowex 2, Amberlite IRA-400 and Amberiite IRA-410. These resins arepolyquaternary ammonium compounds in which the quaternary ammoniumgroups are attached to a styrene-divinylbenzene copolymer. Such resinsare prepared for example, by chloromethylating the copolymer and thentreating it with an alkyl halide such as trimethylamine ordimethylethanolamine. The soobtained solution of the substitutedammonium hydroxide corresponding to one of the salts of this inventionis then neutralized with the acid corresponding to the desired anion.Alternatively, one of the above substituted mono-ammonium halides ofthis invention may be treated directly with the silver salt of the acidcorresponding to the desired anion in an aqueous alcoholic solution. Thesilver halide precipitates and can be separated from the product.

The ability of these compounds to bring about a therapeutically usefulreduction in blood pressure was determined in cats anesthetized withchloralose by canulating the carotid artery and recording the bloodpressure on a kymograph after subjecting the cat to various stimuli. Theganglionic blocking activity was determined by measuring the ability ofthese materials to abolish or decrease the response of the nictitatingmembrance to a standard preganglionic electrical stimulation in thesuperior cervical ganglion preparation of the cat as well as theirability to block the stimulating effect on the ganglia of thetetramethylammonium ion. Stimulation of the ganglia in the latterfashion is manifested by a rise in blood pressure and a contraction ofthe nictitating membrance as well as other pharmacodynamic effects. Allof the above compounds were found in these tests to be highly etfectivein reducing the blood pressure. That is each was found to possessganglionic blocking activity, or direct vasodilator activity or acombination thereof which elfected a significant reduction in theanimals blood pressure.

With regard to possible side effects of these materials afiecting eitherthe heart or the neuro-muscular transmission, further tests were carriedout. The cardiac effects were measured in the isolated perfused catsheart according to the Langendorf method. The coronary inflow wasmeasured with a fiowmeter, and the contractile force and rate wererecorded with the inkwriting recorder. In a hypotensive drug, a decreasein any of these activities is undesirable since it reflectscardio-toxicity of the drug. While an increase in coronary inflow isdesirable, it is not a necessary prerequisite for a useful drug. None ofthe valuable mono-ammonium salts of the present invention was found toelicit the above manifestations of cardiotoxicity to a harmful degree.Some actually had a favorable type of action. Neuro-muscular blocking orcurariform activity was measured in the gastrocnemius preparation of theguinea pig. The activity of these compounds was compared with that ofd-tubocurarine. None was found to possess more than 4% of the activityof d-tubocurarine.

The valuable hypotensive agents of this invention may be administered byvarious routes. In the animal experiments described above, however,intravenous administration was found to be the most convenient. Thesevaluable agents are relatively toxic materials exhibiting acuteintravenous toxicities in the range of about 10-40 mg./ kg. However,very small doses of these substances are required. Intravenous doses inthe range 0.5-4.0 mg./kg. were found to be effective. Doses of the orderof 1 mg./kg. or less were commonly used. Thus the therapeutic index issufiiciently high to make these materials safe to use.

These compounds may be combined with various pharmaceutical carries thechoice of which depends upon the properties of the particular compoundsand upon the route of administration. For intravenous administration, itis convenient to employ the compounds in the form of dilute solutionseither in water or in aqueous solutions isotonic in glucose or sodiumchloride.

The following examples are given to illustrate the preparation ofspecific compounds of this invention. They are presented forillustrative purposes only and are not to be considered as limiting theinvention in any way.

Example I.Substituted ammonium salts The bulk of the substitutedammonium salts referred to herein Were prepared by refluxing the basewith the quaterresults obtained for each of the compounds prepared bythis type of procedure are summarized in the accompanying table. In thisparticular series of compounds, the bases employed in preparing thesequarternary salts were harman, 1,2-dimethy1-1,2,3,4-tetrahydro-8-carboline, and 1,2 dimethyl-7-methoxy-l,2,3,4-tetrahydro-p-carboline.

SUBSTITUTED AMMONIUM SALTS PREPARED BY THE PROCEDURE OF EXAMPLE IAnalysis No. Compound M.P.,C. Reeryst. solvent Calculated Found H N X 0H N X NR x -CH: OCH; Br assumes M on 62.67 5.00 1.31 62 .56 5.18 6.97

2 CHzGOaCH| Br 209-210 MeOH 53.74 4.51 8.36 23.84 53.47 4.50 8.38 23.79

Compound G9 0H. N\ x N H R R R X CH OCH; H Br 180-181 MeOH-MeaGO-.-62.84 6.28 6.98 62.65 6.60 6.68

4 OH. H (31 199-201 MeOH-MezOO-.- 70.67 7.06 7.85 9.94 70.64 7.47 7.4710.00

OCH:

OCH: l

-cm@ H m 188-189 Not recryst 62.84 6.28 6.98 62.25 6.21 6.84

6---- -OH H Br 179-180 .....(10 54.57 4.81 6.36 54.94 5.24 6.15

7.--- --CHUOCH= OOH; Br 177-178.5 61,25 6.31 6.49 61.85 6.33 6.27

Example II.1,2-dimethyZ-7-meth xy-1 ,2,3,4-tetrahydro- S-carbolineHarmaline methosulfate, 6.77 g., dissolved in 120 ml. of methanol wasadded to a solution of 3.78 g. of sodium borohydride and 1.33 g. ofsodium hydroxide dissolved in ml. of methanol. The mixture was refluxedfor 2 hours and a further 1.99 g. of sodium borohydride and 20 ml. ofmethanol was added. The solution was refluxed for an additional threehours after which time the yellow color had faded. The solvent wasremoved and ether and Water were added to the residue. The layers wereseparated and the water layer extracted several times with additionalportions of ether. The comchloride solution, dried over magnesiumsulfate and concentrated until crystals separated. The product weighed6.32 g. and had a melting point of 177-l79 C. It was a white crystallinesolid which could be recrystallized from ethanol and acetone. Ananalytical sample so prepared had a melting point of 1775-1785.

Analysis.-Calculated for C H ON C, 73.01; H, 7.88; N, 12.17. Found: C,72.99; H, 7.98; N. 12.19.

Example III.1-methyl 2 (m-merhoxybenzyl)-1,2,3,4-

tetrahydrO-fi-carbqline hydrocr'iloride A solution of 12.1 grams ofsodium borohydridein 100 ml. of methanol was slowly added to a slurry of16 bined ether extracts were washed with an aqueous sodium g. of" them-methoxybenzyl bromide salt of barman (Example Icompound No. 1 in thetable) in 200 m1. of methanol. The mixture was refiuxed with stirringfor six hours, the methanol evaporated, and the residue treated withwater and ether. The layers were separated and the ether and the waterlayer extracted with several additional portions of ether. The extractswere dried over magnesium sulfate and the solvent removed yielding 13.6g. of crude 1-methyl-2-(m-methoxybenzyl)-1,2,3,4-tetrahydro-p-carboline.This material was dissolved in dry ether and treated with an excess ofmethanolic hydrogen chloride. The hydrochloride salt of the base wasprecipitated by treating the solution with acetone. The crude productwas recrystallized from a mixture of methanol and acetone yielding whiteneedles, melting point 226--226.5 C.

Analysis-Calculated for C H ON Cl: C, 70.06; H, 6.47; N, 8.17. Found: C,69.85; H, 6.60; N, 8.19.

Example IV.1-methyl-2-(Z-diethylaminoethylcarbamylmethyl)-fi-carb0liniumbromide Z-Carbomethyloxymethyl harmanium bromide (Example l-compound No.2 in the table), 2.01 g. was refluxed with 3.48 g. of drydiethylaminoethylamine in 30 ml. of anhydrous methanol for 4 hours. Thesolution was concentrated and the product precipitated by treatment ofthe concentrate with benzene. It was a light yellow solid which wascollected, washed with benzene and ether and recrystallized from acetoneand methanol. Its melting point was 189-l90 C.

10 Analysis-Calculated for C H ON Br: C, 57.28; H, 6.49; N, 13.36.Found: C, 56.83; H, 6.37; N, 13.19.

What is claimed is: 1. A compound having the formula wherein R isselected from the group consisting of a lower hydrocarbonoxy groupcontaining up to six carbon atoms and the -NHCH CH NL group wherein L isa lower alkyl group containing up to three carbon atoms; and X is apharmacologically acceptable anion.

2. A therapeutic composition comprising a compound as claimed in claim 1and a pharmaceutical carrier therefor.

3. A method for reducing the blood pressure comprising the step ofadministering to the host a compound as claimed in claim 1.

4. 1 Methyl 2 (2 diethylaminoethylcarbamylmethyD-fl-carbolinium bromide.

5. 1 Methyl 2 (carbomethoxymethyl) 9 carbolinium bromide.

No references cited.

1. A COMPOUND HAVING THE FORMULA